The immune system modulates the initial response to biomaterial implantation, but which biomaterial characteristics control the inflammatory response is unknown. The long-term goal is to understand the signaling pathways used by innate immune cells in biomaterial recognition and inflammatory processes that lead to tissue healing and regeneration. The objective of this proposal is to determine the role of Wnt signaling in the response to biomaterial surface characteristics, inflammatory response, and recruitment of stem and immune cells. The central hypothesis is that macrophages regulate bone healing through autocrine phenotype modulation and secretion of Wnt ligands into the injury microenvironment, modulating the recruitment and activity of stem and immune cells. The rationale underlying this proposal is to identify key Wnt proteins and signaling pathways that can be targeted to modulate and ameliorate the inflammatory process that occurs after biomaterial implantation. The proposed work will also identify key physical and chemical components of biomaterial surfaces that control macrophage activation and function. The central hypothesis will be tested through three aims: 1) Establish the role of Wnt signaling in macrophage activation and inflammatory response on clinically relevant implant materials; 2) Establish the autocrine and paracrine effect of Wnt proteins in macrophage activation, macrophage/MSC crosstalk, and immune cell recruitment; 3) Elucidate the mechanism of macrophage activation and Wnt secretion in response to biomaterial surface properties. We will pursue these aims using a combination of in vitro and in vivo studies with conditional transgenic knockouts of Wnt signaling pathways in macrophages. The study of Wnt signaling on macrophage behavior and as an orchestrator of the inflammatory response is innovative and has not been explored in the context of biomaterial implantation. The proposed work is significant because it will determine the role of Wnt proteins and signaling in macrophage activation and the production of the inflammatory microenvironment. It is also significant because it will provide scientific evidence of the importance of Wnt signaling on the inflammatory milieu that can be translated in the long term into other areas such as chronic inflammatory diseases and cancer. The proximate expected outcome of this work is the understanding of Wnt signaling in macrophage activation and its contribution on the inflammatory and healing process in response to biomaterial surface characteristics. Results form this proposal will have important immediate positive impact establishing the role of Wnt signaling in macrophage activation and inflammatory response providing key targets for modulation of this activation and inflammatory response.